Programmable DNA Scaffolds Enable Orthogonal Engineering of Cell Membrane-Based Nanovesicles for Therapeutic Development.

Cell membrane-based nanovesicles (CMNVs) play pivotal roles in biomolecular transportation in living organisms and appear as attractive bioinformed nanomaterials for theranostic applications. However, the current surface-engineering technologies are limited in flexibility and orthogonality, making it challenging to simultaneously display multiple different ligands on the CMNV surface in a precisely controlled manner. Here, we developed a DNA scaffold-programmed approach to orthogonally engineer CMNVs with versatile ligands. The designed DNA scaffolds can rapidly anchor onto the CMNV surface, and their unique sequences and hybridized properties enable independent control of the loading of multiple different types of biomolecules on the CMNVs. As a result, the orthogonal engineering of CMNVs with a renal targeted peptide and a therapeutic protein at controlled ratios demonstrated an enhanced renal targeting and repair potential in vivo. This study highlights that a DNA scaffold-programmed platform can provide a potent means for orthogonal and flexible surface engineering of CMNVs for diverse therapeutic purposes.

Injectable Multifunctional Composite Hydrogel as a Combination Therapy for Preventing Postsurgical Adhesion.

Postsurgical adhesion (PA) is a common and serious postoperative complication that affects millions of patients worldwide. However, current commercial barrier materials are insufficient to inhibit diverse pathological factors during PA formation, and thus, highly bioactive materials are needed. Here, this work designs an injectable multifunctional composite hydrogel that can serve as a combination therapy for preventing PA. In brief, this work reveals that multiple pathological events, such as chronic inflammatory and fibrotic processes, contribute to adhesion formation in vivo, and such processes can not be attenuated by barrier material (e.g., hydrogel) alone treatments. To solve this limitation, this work designs a composite hydrogel made of the cationic self-assembling peptide KLD2R and TGF-ß receptor inhibitor (TGF-ßRi)-loaded mesenchymal stem cell-derived nanovesicles (MSC-NVs). The resulting composite hydrogel displays multiple functions, including physical separation of the injured tissue areas, antibacterial effects, and local delivery and sustained release of anti-inflammatory MSC-NVs and antifibrotic TGF-ßRi. As a result, this composite hydrogel effectively inhibited local inflammation, fibrosis and adhesion formation in vivo. Moreover, the hydrogel also exhibits good biocompatibility and biodegradability in vivo. Together, the results highlight that this "all-in-one" composite hydrogel strategy may provide insights into designing advanced therapies for many types of tissue injury.

A co-adaptive duality-aware framework for biomedical relation extraction.

MOTIVATION: Biomedical relation extraction is a vital task for electronic health record mining and biomedical knowledge base construction. Previous work often adopts pipeline methods or joint methods to extract subject, relation, and object while ignoring the interaction of subject-object entity pair and relation within the triplet structure. However, we observe that entity pair and relation within a triplet are highly related, which motivates us to build a framework to extract triplets that can capture the rich interactions among the elements in a triplet. RESULTS: We propose a novel co-adaptive biomedical relation extraction framework based on a duality-aware mechanism. This framework is designed as a bidirectional extraction structure that fully takes interdependence into account in the duality-aware extraction process of subject-object entity pair and relation. Based on the framework, we design a co-adaptive training strategy and a co-adaptive tuning algorithm as collaborative optimization methods between modules to promote better mining framework performance gain. The experiments on two public datasets show that our method achieves the best F1 among all state-of-the-art baselines and provides strong performance gain on complex scenarios of various overlapping patterns, multiple triplets, and cross-sentence triplets. AVAILABILITY AND IMPLEMENTATION: Code is available at https://github.com/11101028/CADA-BioRE.

Integration of multiple terminology bases: a multi-view alignment method using the hierarchical structure.

MOTIVATION: In the medical field, multiple terminology bases coexist across different institutions and contexts, often resulting in the presence of redundant terms. The identification of overlapping terms among these bases holds significant potential for harmonizing multiple standards and establishing unified framework, which enhances user access to comprehensive and well-structured medical information. However, the majority of terminology bases exhibit differences not only in semantic aspects but also in the hierarchy of their classification systems. The conventional approaches that rely on neighborhood-based methods such as GCN may introduce errors due to the presence of different superordinate and subordinate terms. Therefore, it is imperative to explore novel methods to tackle this structural challenge. RESULTS: To address this heterogeneity issue, this paper proposes a multi-view alignment approach that incorporates the hierarchical structure of terminologies. We utilize BERT-based model to capture the recursive relationships among different levels of hierarchy and consider the interaction information of name, neighbors, and hierarchy between different terminologies. We test our method on mapping files of three medical open terminologies, and the experimental results demonstrate that our method outperforms baseline methods in terms of Hits@1 and Hits@10 metrics by 2%. AVAILABILITY AND IMPLEMENTATION: The source code will be available at https://github.com/Ulricab/Bert-Path upon publication.

Macrophage-derived exosomal miR-195a-5p impairs tubular epithelial cells mitochondria in acute kidney injury mice.

Macrophages (Mφ) infiltration is a common characteristic of acute kidney injury (AKI). Exosomes-mediated cell communication between tubular epithelial cells (TECs) and Mφ has been suggested to be involved in AKI. Exosomes-derived from injured TECs could regulate Mφ polarization during AKI. However, little is known regarding how activated Mφ regulates kidney injury. To explore the role of activated Mφ in the AKI process, we revealed that Mφ-derived exosomes from AKI mice (ExosAKI ) caused mitochondria damage and induced TECs injury. Then, we detected the global miRNA expression profiles of MφNC and MφAKI and found that among the upregulated miRNAs, miR-195a-5p, which regulates mitochondria metabolism in cancer, was significantly increased in MφAKI . Due to the enrichment of miR-195a-5p in ExosAKI , the miR-195a-5p level in the kidney was elevated in AKI mice. More interestingly, based on the high expression of pri-miR-195a-5p in kidney-infiltrated Mφ, and the reduction of miR-195a-5p in kidney after depletion of Mφ in AKI mice, we confirmed that miR-195a-5p may be produced in infiltrated Mφ, and shuttled into TECs via ExosMφ . Furthermore, in vitro inhibition of miR-195a-5p alleviated the effect of ExosAKI induced mitochondrial dysfunction and cell injury. Consistently, antagonizing miR-195a-5p with a miR-195a-5p antagomir attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. These findings revealed that the Mφ exosomal miR-195a-5p derived from AKI mice played a critical pathologic role in AKI progression, representing a new therapeutic target for AKI.

Deciphering cuproptosis-related signatures in pediatric allergic asthma using integrated scRNA-seq and bulk RNA-seq analysis.

OBJECTIVE: Allergic asthma (AA) is common in children. Excess copper is observed in AA patients. It is currently unclear whether copper imbalance can cause cuproptosis in pediatric AA. METHODS: The datasets about pediatric AA (GSE40732 and GSE40888) were obtained from Gene Expression Omnibus (GEO) database. The expression of cuproptosis-related genes (CRGs) and immune cell infiltration in pediatric AA samples were analyzed. Single-cell RNA sequencing (scRNA-seq) data (GSE193816) were used to evaluate the expression patterns of CRGs in AA. The identification of differentially expressed genes within clusters was conducted using weighted gene co-expression network analysis. Subsequently, disease progression and cuproptosis-related models were screened using random forest (RF), support vector machine (SVM), extreme gradient boosting (XGBoost), and general linear model (GLM) algorithms. RESULTS: Four CRGs were notably increased in pediatric AA samples. CD4+ T cells, macrophages and mast cells exhibited a lower cuproptosis score in AA samples, indicating that these immune cells may be closely associated with cuproptosis in AA development. Co-expression network of CRGs in AA was constructed. AA samples were divided into two cuprotosis clusters. Following construction of four machine-learning models, SVM model exhibited the highest efficacy of prediction in the testing set (AUC = 0.952). SVM model containing five important variables can be used for prediction of AA. CONCLUSION: This work provided a machine learning model containing five important variables, which may have good diagnostic efficiency for pediatric AA.

PLS3 promotes papillary thyroid carcinoma progression by activating the Notch signaling pathway.

Thyroid cancer is the most common endocrine malignancy worldwide. Although significant progress has been made in understanding the genetic and molecular alterations that drive thyroid cancer, the mechanisms underlying thyroid tumor progression remain unclear. In this study, we explored the involvement of Plastin-3 (PLS3) in the progression of papillary thyroid cancer and elucidated the underlying molecular mechanisms. We first analyzed clinical samples from papillary thyroid cancer patients and found that PLS3 expression was significantly upregulated in tumor tissues compared to adjacent normal tissues. Moreover, high PLS3 expression was associated with advanced tumor stage and poor prognosis. Further in vitro and in vivo experiments showed that PLS3 could promote the proliferation, migration, and invasive behavior of papillary thyroid cancer cells, while PLS3 knockdown suppressed these processes. Mechanistically, we found that PLS3 promoted papillary thyroid cancer progression by activating the Notch signaling pathway. Specifically, PLS3 upregulated the expression of Notch receptors (Notch1) and downstream target gene (Hes1) in papillary thyroid cancer cells. In summary, our findings collectively indicate that PLS3 plays a pivotal role in driving the progression of papillary thyroid cancer and holds promise as a viable therapeutic target for the treatment of this disease.

Identification and characteristic analysis of semi-natural habitats in China's economically developed areas: New insights to inform cultivated land system ecological conservation.

Identifying and characterizing semi-natural habitats (SNHs) are important to the ecological conservation of cultivated land systems and implementing China's ecological civilization strategy. This study revealed the concept and characteristics of SNHs in Chinese cultivated land systems regarding human activities, resource types, and spatial landscape patterns. The resource quantity, landscape quality, and spatial distribution of SNHs in Southern Jiangsu's cultivated land system were analyzed by constructing the identification model of "land use/land cover type-cultivated land use intensity-spatial landscape pattern". The results showed that the area of SNHs in Southern Jiangsu's cultivated land system was 25.35%, significantly influenced by cultivated land intensification and expansion. The higher the cultivated land use intensity, the lower the quantity of SNHs, and the proportion of SNHs in the intensive-use pattern was only 2.97%. 68.18% of the SNHs in Southern Jiangsu were water, and habitats for important species, such as woodland, grassland, wetlands, and bare land, were scarce. A small patch area, high landscape fragmentation, poor landscape richness and diversity, and low connectivity accompanied increased cultivated land use intensity. From the extensive to intensive utilization, the spatial spread of SNHs from low-value aggregation to high-value scatter areas, with hotspot areas of cultivated land use intensity and SNHs existing only in a small part of Nanjing and Changzhou. This study provides a scientific reference for the rehabilitation and restoration of SNHs in the context of the ecological transformation of land use. It promotes the sustainable intensification of cultivated land systems. It also provides new ideas for linking ecological and urban spaces to form a stable and systematic national ecological safety network.

Effect of Chemical Composition of Metal-Organic Crosslinker on the Properties of Fracturing Fluid in High-Temperature Reservoir.

To investigate the effect of the chemical composition of a metal-organic crosslinker on the performances of fracturing fluid in high-temperature conditions, four zirconium (Zr) crosslinkers and one aluminum-zirconium (Al-Zr) crosslinker with a polyacrylamide were used. The crosslinkers possessed the same Zr concentration, but they differed in component amounts and the order of the addition of the crosslinker components, leading to different chemical compositions in the crosslinkers. The fracturing fluids prepared by different tested crosslinkers were compared in terms of properties of rheological behavior, sand-carrying ability, microstructure, and gel breaking characteristics. The results showed that the fracturing fluids prepared by zirconium lactic acid, ethanediamine, and sorbitol crosslinkers offered the slowest viscosity development and highest final viscosity compared to the zirconium lactic acid crosslinker and the zirconium lactic acid and ethanediamine crosslinker. The zirconium sorbitol, lactic acid, and ethanediamine crosslinker exhibited a faster crosslinking rate and a higher final viscosity than the zirconium lactic acid, ethanediamine, and sorbitol crosslinker; the crosslinker showed crosslinking density and crosslinking reactivity, resulting in more crosslinking sites and a higher strength in the fracturing fluid. The Al-Zr-based crosslinker possessed better properties in temperature and shear resistance, viscoelasticity, shear recovery, and sand-carrying ability than the Zr-based crosslinker due to the synergistic crosslinking effect of aluminum and zirconium ions. The tertiary release gelation mechanism of the Al-Zr-based fracturing fluid achieved a temperature resistance performance in the form of continuous crosslinking, avoiding the excessive crosslinking dehydration and reducing viscosity loss caused by early shear damage. These results indicated that the chemical compositions of metal-organic crosslinkers were important factors in determining the properties of fracturing fluids. Therefore, the appropriate type of crosslinker could save costs without adding the additional components required for high-temperature reservoirs.

S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis.

Senescence of bone marrow mesenchymal stem cells (BMSCs) is one of the leading causes of osteoporosis. SIRT3, an essential NAD-dependent histone deacetylase, is highly correlated with BMSC senescence-mediated bone degradation and mitochondrial/heterochromatic disturbance. S-sulfhydration of cysteine residues favorably enhances SIRT3 activity by forming persulfides. Nevertheless, the underlying molecular mechanism of SIRT3 S-sulfhydration on mitochondrial/heterochromatic homeostasis involved in BMSC senescence remains unknown. Here, we demonstrated that CBS and CSE, endogenous hydrogen sulfide synthases, are downregulated with BMSC senescence. Exogenous H2S donor NaHS-mediated SIRT3 augmentation rescued the senescent phenotypes of BMSCs. Conversely, SIRT3 deletion accelerated oxidative stress-induced BMSC senescence through mitochondrial dysfunction and the detachment of the heterochromatic protein H3K9me3 from the nuclear envelope protein Lamin B1. H2S-mediated SIRT3 S-sulfhydration modification rescued the disorganized heterochromatin and fragmented mitochondria induced by the S-sulfhydration inhibitor dithiothreitol, thus leading to elevated osteogenic capacity and preventing BMSC senescence. The antisenescence effect of S-sulfhydration modification on BMSCs was abolished when the CXXC sites of the SIRT3 zinc finger motif were mutated. In vivo, aged mice-derived BMSCs pretreated with NaHS were orthotopically transplanted to the ovariectomy-induced osteoporotic mice, and we proved that SIRT3 ameliorates bone loss by inhibiting BMSC senescence. Overall, our study for the first time indicates a novel role of SIRT3 S-sulfhydration in stabilizing heterochromatin and mitochondrial homeostasis in counteracting BMSC senescence, providing a potential target for the treatment of degenerative bone diseases.

Development and Application Evaluation of a Nursing Simulation Teaching Information System Based on Hospital Information Systems.

Background: The extensive application of hospital information systems in the current information-driven era suggests that nursing education should focus on information education. Methods: The newly developed hospital information system was used and evaluated by 544 students to explore the feasibility and necessity of such applications for teaching. Results: Overall, 97.1% of the students expressed satisfaction, and 96.0% supported simulated information education for nursing. The usability was good, with the system receiving a usability score of 72.625 ± 13.0907. The junior students had a higher score than the sophomores regarding system availability, and the difference was statistically significant. Conclusions: Students generally had a high degree of satisfaction with the simulated information nursing education system and highly approved of the teaching method. However, the system needs to be upgraded.

Design of Miniaturized Wideband Beam Deflection Conformal Array Antenna.

Antenna beam deflection, along with miniaturization and wideband of the antenna is in demand for practical applications. In this paper, a cylindrical conformal array antenna with a small-tilt forward beam was designed. The microstrip antenna unit was loaded with the artificial electromagnetic structure, which reduced the size of the antenna unit. As a result, the center spacing of the array elements can be shortened with the same array element spacing. The beam deflection angle can be increased in this way without increasing the coupling effect between the parts. Changing the number of line array elements and the number of line arrays can regulate the beam width of E-field and H-field, respectively. The bandwidth of the antenna can be significantly extended by slotting the ground plane. This work implemented a cylindrical conformal array of the antenna's forward beam with a small dip angle using a cylindrical carrier as an example. The measurement results showed that the angle between the main beam and the carrier axis of the conformal antenna was less than 30°, the bandwidth was more than 30%, and the antenna volume decreased by 40.4%.

The role of harmonized Landsat Sentinel-2 (HLS) products to reveal multiple trajectories and determinants of cropland abandonment in subtropical mountainous areas.

Cropland abandonment is a widespread land-change process globally, which can stem from the accelerated outmigration of the population from rural to urban areas, socio-economic and political changes, catastrophes, and other trigger events. Clouds limit the utility of optical satellite data to monitor cropland abandonment in highly fragmented mountain agricultural landscapes of tropical and subtropical regions, including the south of China. Taking Nanjing County of China as an example, we developed a novel approach by utilizing multisource satellite (Landsat and Sentinel-2) imagery to map multiple trajectories of cropland abandonment (transitioning from cropland to grassland, shrubs and forest) in subtropical mountainous landscapes. Then, we employed a redundancy analysis (RDA) to identify the spatial association of cropland abandonment considering agricultural productivity, physiography, locational characteristics and economic factors. Results indicate the great suitability of harmonized Landsat 8 and Sentinel-2 images to distinguish multiple trajectories of cropland abandonment in subtropical mountainous areas. Our framework of mapping cropland abandonment resulted in good producer's (78.2%) and user's (81.3%) accuracies. The statistical analysis showed 31.85% of croplands cultivated in 2000 were abandoned by 2018, and more than a quarter of townships experienced cropland abandonment with high abandoned rates (>38%). Cropland abandonment mainly occurred in relatively unfavorable areas for agricultural production, for instance with a slope above 6°. Slope and the proximity to the nearest settlement explained 65.4% and 8.1% of the variation of cropland abandonment at the township level, respectively. The developed approaches on both mapping cropland abandonment and modeling determinants can be highly relevant to monitor multiple trajectories of cropland abandonment and ascribe their determinants not only in mountainous China but also elsewhere and thus promote the formulation of land-use policies that aim to steer cropland abandonment.

Fracturing Fluid Polymer Thickener with Superior Temperature, Salt and Shear Resistance Properties from the Synergistic Effect of Double-Tail Hydrophobic Monomer and Nonionic Polymerizable Surfactant.

To develop high-salinity, high-temperature reservoirs, two hydrophobically associating polymers as fracturing fluid thickener were respectively synthesized through aqueous solution polymerization with acrylamide (AM), acrylic acid (AA), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), nonionic polymerizable surfactant (NPS) and double-tail hydrophobic monomer (DHM). The thickener ASDM (AM/AA/AMPS/NPS/DHM) and thickener ASD (AM/AA/AMPS/DHM) were compared in terms of properties of water dissolution, thickening ability, rheological behavior and sand-carrying. The results showed that ASDM could be quickly diluted in water within 6 min, 66.7% less than that of ASD. ASDM exhibited salt-thickening performance, and the apparent viscosity of 0.5 wt% ASDM reached 175.9 mPa·s in 100,000 mg/L brine, 100.6% higher than that of ASD. The viscosity of 0.5 wt% ASDM was 85.9 mPa·s after shearing for 120 min at 120 °C and at 170 s-1, 46.6% higher than that of ASD. ASDM exhibited better performance in thickening ability, viscoelasticity, shear recovery, thixotropy and sand-carrying than ASD. The synergistic effect of hydrophobic association and linear entanglement greatly enhancing the performance of ASDM and the compactness of the spatial network structure of the ASDM was enhanced. In general, ASDM exhibited great potential for application in extreme environmental conditions with high salt and high temperatures.

Adiponectin gene therapy prevents islet loss after transplantation.

Significant pancreatic islet dysfunction and loss shortly after transplantation to the liver limit the widespread implementation of this procedure in the clinic. Nonimmune factors such as reactive oxygen species and inflammation have been considered as the primary driving force for graft failure. The adipokine adiponectin plays potent roles against inflammation and oxidative stress. Previous studies have demonstrated that systemic administration of adiponectin significantly prevented islet loss and enhanced islet function at post-transplantation period. In vitro studies indicate that adiponectin protects islets from hypoxia/reoxygenation injury, oxidative stress as well as TNF-α-induced injury. By applying adenovirus mediated transfection, we now engineered islet cells to express exogenous adiponectin gene prior to islet transplantation. Adenovirus-mediated adiponectin transfer to a syngeneic suboptimal islet graft transplanted under kidney capsule markedly prevented inflammation, preserved islet graft mass and improved islet transplant outcomes. These results suggest that adenovirus-mediated adiponectin gene therapy would be a beneficial clinical engineering approach for islet preservation in islet transplantation.

TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSCs activation and protect against necrotizing enterocolitis.

Intestinal trefoil factor 3 (TFF3) plays an important role in repairing the intestinal mucosa. However, the detailed mechanism regarding immune regulation by TFF3 is not well defined. Here, we reported that treatment of mouse BM cells and human peripheral blood mononuclear cells from healthy volunteers with TFF3 activated polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) in vitro. We also found that prostaglandin E2 is a major TFF3-mediated MDSC target, and that NF-κB/COX2 signaling was involved in this process. Moreover, TFF3 treatment or transfer of TFF3-derived PMN-MDSCs (TFF3-MDSCs) to experimental necrotizing enterocolitis (NEC) mice caused PMN-MDSC accumulation in the lamina propria (LP), which was associated with decreased intestinal inflammation, permeability, bacterial loading, and prolonged survival. Interestingly, no NEC severity remission was observed in Rag1 KO mice that were given TFF3-MDSCs, but coinjection with CD4+ T cells significantly relieved NEC inflammation. Overall, TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSC activation and attenuates NEC in a T-cell-dependent manner, which suggests a novel mechanism in preventing NEC occurrence.

Mitochondrial transfer from mesenchymal stem cells to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation.

Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mφ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy (DN) mice via improving mitochondrial function of Mφ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a coculture system consisting of MSCs and Mφ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mφ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose-induced Mφ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mφ, the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mφ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mφ (MφMito ) inhibited the inflammatory response and alleviated kidney injury. However, the kidney-protective effects of MφMito were abolished when the MSCs-Mito was impaired with rotenone, and the similar results were also observed when MφMito were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mφ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy.

Complement C5 activation promotes type 2 diabetic kidney disease via activating STAT3 pathway and disrupting the gut-kidney axis.

Diabetic kidney disease (DKD) is a severe DM complication. While complement C5 up-regulation and gut dysbiosis are found in T2DM, their roles in DKD are unclear. Here, we investigated the effect of C5 on the gut microbiota during DKD development. Renal C5a/C5a receptor (C5aR) expression changes were measured in T2DM patients and db/db mice. Db/db mice were treated with a C5aR antagonist (C5aRA), and renal function, gut microbiota and renal genome changes were analysed. The effects of C5a and short-chain fatty acids (SCFAs) on the signal transducer and activator of transcription 3 (STAT3) pathway were examined in vitro. C5a was up-regulated in glomerular endothelial cells (GECs) of T2DM patients and db/db mice. Although glucose and lipid metabolism were unchanged, C5aR blockade alleviated renal dysfunction, ECM deposition, macrophage infiltration and proinflammatory factor expression in db/db mice. C5aRA partly reversed the declines in gut microbiota diversity and abundance and gut SCFA levels in db/db mice. C5aRA down-regulated the expression of many immune response-related genes, such as STAT3, in db/db mouse kidneys. C5aRA and SCFAs suppressed C5a-induced STAT3 activation in human renal glomerular endothelial cells (HRGECs). Based on our results, C5 hyperactivation promotes DKD by activating STAT3 in GECs and impairing the gut-kidney axis, suggesting that this hyperactivation is a potential target for the treatment of DKD.

Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury.

Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

Mesenchymal stromal cells protect hepatocytes from lipotoxicity through alleviation of endoplasmic reticulum stress by restoring SERCA activity.

The aim of this study was to investigate how mesenchymal stromal cells (MSCs) modulate metabolic balance and attenuate hepatic lipotoxicity in the context of non-alcoholic fatty liver disease (NAFLD). In vivo, male SD rats were fed with high-fat diet (HFD) to develop NAFLD; then, they were treated twice by intravenous injections of rat bone marrow MSCs. In vitro, HepG2 cells were cocultured with MSCs by transwell and exposed to palmitic acid (PA) for 24 hours. The endoplasmic reticulum (ER) stressor thapsigargin and sarco/ER Ca2+ -ATPase (SERCA2)-specific siRNA were used to explore the regulation of ER stress by MSCs. We found that MSC administration improved hepatic steatosis, restored systemic hepatic lipid and glucose homeostasis, and inhibited hepatic ER stress in HFD-fed rats. In hepatocytes, MSCs effectively alleviated the cellular lipotoxicity. Particularly, MSCs remarkably ameliorated the ER stress and intracellular calcium homeostasis induced by either PA or thapsigargin in HepG2 cells. Additionally, long-term HFD or PA stimulation would activate pyroptosis in hepatocytes, which may contribute to the cell death and liver dysfunction during the process of NAFLD, and MSC treatment effectively ameliorates these deleterious effects. SERCA2 silencing obviously abolished the ability of MSCs against the PA-induced lipotoxicity. Conclusively, our study demonstrated that MSCs were able to ameliorate liver lipotoxicity and metabolic disturbance in the context of NAFLD, in which the regulation of ER stress and the calcium homeostasis via SERCA has played a key role.